Disease models and AAV therapies of PKP2-induced arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM) is most commonly associated with pathogenic variants in the desmosomal gene plakophilin-2 (PKP2). However, PKP2-induced ACM remains challenging to decipher due to the multifaceted roles of its protein product, plakophilin-2 (PP2). This review provides a comparative analysis of experimental systems used to model PKP2-induced ACM, including in vivo, ex vivo, and in vitro animal models, as well as human induced pluripotent stem cell (hiPSC)-derived mono- and multicellular models. These models have revealed key insights into the roles of desmosomal dysfunction, lipid accumulation, and electrical instability during disease progression. Notably, therapeutic strategies aimed at restoring PKP2 expression through adeno-associated virus (AAV) gene therapy have demonstrated promising results, suggesting a potential therapeutic approach for ACM. Notwithstanding these advances, challenges persist, including discrepancies between models, limited cardiomyocyte-specific models, and the need for further elucidation of the molecular pathways. This review emphasizes the importance of refining models to better capture the molecular landscape of PKP2-induced ACM, to enable improved mechanistic insight and the development of targeted therapies.